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Palbociclib Plus Letrozole in Hormone Receptor Positive Residual Disease After Neoadjuvant Chemotherapy

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ClinicalTrials.gov Identifier: NCT04130152
Recruitment Status : Not yet recruiting
First Posted : October 17, 2019
Last Update Posted : October 17, 2019
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
SOLTI Breast Cancer Research Group

Brief Summary:
PROMETEO II is a single-arm window of opportunity trial to evaluate biologic and anti-proliferative effects of palbociclib and letrozole in HR+/HER2-negative operable breast cancer (BC) patients with residual disease after neoadjuvant chemotherapy (NAC) and help to identify biomarkers for better patient selection.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Palbociclib Drug: Letrozole Early Phase 1

Detailed Description:

This is a single-arm window of opportunity trial to evaluate biologic and anti-proliferative effects of palbociclib and letrozole in HR+/HER2-negative operable BC patients with residual disease after NAC and help to identify biomarkers for better patient selection.

The primary endpoint will be the Complete Cell Cycle Arrest (CCCA) determined by Ki67<2.7%, centrally assessed at surgery after 4 weeks of palbociclib and letrozole.

Tumor measurement will be performed by magnetic resonance imaging (MRI) for disease evaluation at screening at the end of NAC. The biopsy after chemotherapy will only be done if the tumor is equal or larger than 1 cm in its greatest diameter by MRI. Ki67% ≥ 10% after NAC by local determination will be necessary to be included in the study.

Patients will be administered palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle and letrozole: oral, 2.5 mg per day continuously, one cycle of treatment.

After finalization of the neoadjuvant treatment, patients will undergo surgery. Surgery specimens will be collected for histological examination and biomarker analysis

The end of the study is defined as the date of post-surgery visit and will take place 4 weeks (+/- 7days) after the surgery in order to monitor the patient's safety and collect the surgery information.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Palbociclib in Combination With Letrozole in Patients With Hormone Receptor (HR) Positive/Human Epidermal Growth Factor Receptor 2 (HER2) Negative Residual Disease After Standard Neoadjuvant Chemotherapy (PROMETEO II)
Estimated Study Start Date : October 21, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones

Arm Intervention/treatment
Experimental: Palbociclib + Letrozole

Palbociclib 125 mg once daily, day 1 to day 21, followed by 7 days off treatment in a 28-day cycle Letrozole: oral, 2.5 mg per day continuously. during the 28-day cycle.

If the patient is pre-menopausal, ovarian suppression with luteinizing hormone-releasing hormone (LHRH) analogues (ie, triptorelin 3.75 mg intra-muscular (IM) or Goserelin 3,6 mg SC) must be initiated at least 2 weeks before palbociclib plus letrozole administration.

Drug: Palbociclib
Palbociclib 125 mg once daily, day 1 to day 21, followed by 7 days off treatment in a 28-day cycle
Other Name: Ibrance

Drug: Letrozole
Letrozole: oral, 2.5 mg per day continuously. during the 28-day cycle.




Primary Outcome Measures :
  1. Complete Cell Cycle Arrest (CCCA) [ Time Frame: Ki67 changes will be determined from baseline biopsy at the end of NAC and 4 weeks later at surgery ]
    Complete Cell Cycle Arrest (CCCA) determined by Ki67< 2.7% at surgery following treatment with palbociclib plus letrozole, by central laboratory


Secondary Outcome Measures :
  1. Residual Cancer Burden (RCB) [ Time Frame: At surgery, 4 weeks after palbociclib and letrozole treatment ]
    Rate of RCB score 0 or 1 (RCB 0/1) after neoadjuvant treatment, according to the MD Anderson Cancer Center procedures, as per local assessment

  2. Pathological complete response (pCR) [ Time Frame: At surgery, 4 weeks after palbociclib and letrozole treatment ]
    Rate of pCR (ypT0/TisypN0) defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination at the time of definitive surgery, irrespective of in situ carcinoma in the breast and in the breast and axilla by local evaluation.

  3. Incidence, duration and severity of Adverse Events (AEs) [ Time Frame: Up to 4 weeks ]
    Incidence and severity of treatment-emergent and treatment-related adverse events assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5.0, including dose reductions, delays and treatment discontinuations.


Other Outcome Measures:
  1. Change in gene expression of 752 genes [ Time Frame: Gene expression will be analyzed in pretreated sample and at surgery 4 weeks after palbociclib and letrozole treatment ]
    Gene expression changes of 752 genes in all the patients, between posttreatment and pretreatment samples following therapy with palbociclib and letrozole.

  2. Changes of the PAM50 intrinsic subtypes [ Time Frame: Intrinsic subtype will be evaluated in pretreated sample, after NAC, and at surgery following therapy with palbociclib and letrozole. ]
    To evaluate the changes of the PAM50 intrinsic subtypes between samples

  3. Rate of cell cycle suppression according to breast cancer subtype. [ Time Frame: At surgery, 4 weeks after palbociclib and letrozole treatment ]
    To determine the association between PAM50 intrinsic subtypes and biological response following neoadjuvant treatment

  4. Correlation of rate of cell cycle suppression with gene expression changes of 752 genes. [ Time Frame: Cell cycle suppression and gene expression will be evaluated pretreatment and at surgery 4 weeks after palbociclib and letrozole treatment. ]
    To determine the association between gene expression from pre-treatment samples with biological response after neoadjuvant treatment.

  5. Correlation of pCR and RCB with gene expression changes of 752 genes. [ Time Frame: At surgery, 4 weeks after palbociclib and letrozole treatment ]
    To determine the association between gene expression from pre-treatment samples with pathological response after letrozole and palbociclib treatment.

  6. Changes in tumor-infiltrating lymphocytes (TILs) [ Time Frame: At surgery, 4 weeks after palbociclib and letrozole treatment ]
    Changes in TILs by immunohistochemistry (eg, percentages (%) of stromal TILs) in lesions before and after treatment.

  7. Changes in Programmed death-ligand 1 (PDL1) expression [ Time Frame: At surgery, 4 weeks after palbociclib and letrozole treatment ]
    Changes in PDL1 expression immuno-histochemistry (IHC) in lesions before and after treatment.

  8. Increase in CelTIL score [ Time Frame: At surgery, 4 weeks after palbociclib and letrozole treatment ]

    CelTIL score is a metric for quantifying broad changes to the tumor microenvironment and is calculated by the following equation:

    CelTIL score = −0.8 × tumor cellularity (in percent) + 1.3 × TILs (in percent). The minimum and maximum unscaled CelTIL scores will be −80 and 130. This unscaled CelTIL score will then be scaled to reflect the reported values ranging from 0 to 100 points where an increase in CelTIL scores represent favorable changes to the tumor microenvironment.


  9. Changes in ctDNA [ Time Frame: ctDNA evaluation will be performed post-NAC and at surgery, 4 weeks after palbociclib and letrozole treatment. ]
    Determination of changes in ctDNA in plasma samples



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written and signed informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
  2. Female patients age ≥ 18 years.
  3. Pre and post-menopausal women.
  4. ECOG (Eastern Cooperative Oncology Group) Performance Status of 0 to 1.
  5. Histologically confirmed non-metastatic primary HR-positive/HER2 negative breast cancer with all the following characteristics:

    • Breast cancer eligible for surgery.
    • ER-positive and/or progesterone receptor (PgR) positive and HER2-negative tumor by American Society of Clinical Oncology (ASCO) /College of American Pathologists (CAP) guidelines, ER and PgR defined as IHC nuclear staining >1% and HER2 negative and Ki-67 >10%, locally assessed.
    • Ki67% ≥ 10% after neoadjuvant chemotherapy locally assessed.
    • A lesion that can be accurately and serially measured in at least 1 dimension and for which the longest diameter is ≥ 1 cm as measured by MRI after neoadjuvant chemotherapy.
  6. Completed ≥80% total dose of an anthracycline/taxane-based neoadjuvant regimen planned. The allowed chemotherapy regimens will be AC (cyclophosphamide, doxorubicin) or EC (epirubicin, cyclophosphamide) 4 cycles followed by weekly paclitaxel x 12 or AC or EC 4 cycles followed by docetaxel 4 cycles. It would be acceptable to change the administration sequence to paclitaxel followed by AC/EC. AC can be given either a standard dose or in a dose dense schedule. Paclitaxel could be administered as a solvent-based or Nanoparticle albumin-bound (Nab) formulation.
  7. Availability of a recent formalin-fixed paraffin-embedded (FFPE) tumor sample before NAC and a research tumor biopsy after NAC. Minimal sample requirements are to have at least 2 tumor cylinders with a minimal tissue surface of 10 mm2 tissue, containing at least 10% tumor cells and having enough tissue to do at least 2 cuts of 10 μm each.
  8. Adequate organ function determined within 28 days prior to enrollment, defined as follows:

    • Hematological

      • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
      • Platelet count ≥ 100 x 109/L
      • Hemoglobin ≥ 9 g/dL (red blood cell transfusion and/or erythropoietin allowed)
    • Renal

      • Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or 24-hour creatinine clearance ≥ 60 mL/min for subject with creatinine levels >1.5 x ULN. (Note: Creatinine clearance does not need to be determined if the baseline serum creatinine is within normal limits. Creatinine clearance should be calculated per institutional standard).

    • Hepatic

      • Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total bilirubin level > 1.5 x ULN
      • Aspartate aminotransferase (AST) ≤ 2.5 x ULN
      • Alanine aminotransferase (ALT) ≤ 2.5 x ULN Coagulation International normalization ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN
  9. Serum or urine pregnancy test must be negative within 7 days prior to randomization in women of childbearing potential. If the urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential randomized to the treatment must use adequate contraception for the duration of protocol treatment.
  10. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
  11. Resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE version 5.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).

Exclusion Criteria:

  1. Non-operable, locally advanced breast cancer (inoperable stage III) after NAC.
  2. Bilateral or metastatic invasive breast cancer at the time of the diagnosis.
  3. Multicentric or multifocal breast cancer before NAC.
  4. Known severe hypersensitivity reactions to compounds similar to palbociclib or to excipients or to endocrine treatments.
  5. History of any previous treatment using Aromatase inhibitors (AI) o selective estrogen receptor modulator (SERMs) in the past 5 years.
  6. Prior therapy with palbociclib or any cyclin-dependent kinase (CDK) inhibitor.
  7. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to randomization.
  8. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization.
  9. Any surgery (not including minor procedures such as primary tumor core biopsy, fine needle aspiration) within 4 weeks of start of study treatment; or not fully recovered from any side effects of previous procedures.
  10. Sentinel lymph node biopsy is not allowed before NAC.
  11. Diagnosis of any previous malignancy within the last 3 years, except for adequately treated basal cell carcinoma, or squamous cell skin carcinoma, or in situ cervical carcinoma
  12. Malabsorption syndrome or other condition that would interfere with enteric absorption.
  13. Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
  14. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypomagnesemia).
  15. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
  16. Corrected QT interval (QTc) greater than 480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or know history of QTc prolongation, or Torsade de Pointes (TdP).
  17. Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04130152


Contacts
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Contact: Pamela Celiz, MD, PhD +34638784908 pamela.celiz@gruposolti.org
Contact: Amparo Buenestado, PhD amparo.buenestado@gruposolti.org

Locations
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Spain
Hospital General de Catalunya Not yet recruiting
Barcelona, Spain
ICO Hospitalet Not yet recruiting
Barcelona, Spain
Hospital 12 de octubre Not yet recruiting
Madrid, Spain
Hospital Universitario Infanta Sofía Not yet recruiting
Madrid, Spain
Hospital Virgen de la Victoria Not yet recruiting
Malaga, Spain
Hospital Son Espases Not yet recruiting
Palma De Mallorca, Spain
Complejo Hospitalario Santiago de Compostela (CHUS) Not yet recruiting
Santiago De Compostela, Spain
Hospital Virgen del Rocío Not yet recruiting
Sevilla, Spain
Sponsors and Collaborators
SOLTI Breast Cancer Research Group
Pfizer

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Responsible Party: SOLTI Breast Cancer Research Group
ClinicalTrials.gov Identifier: NCT04130152     History of Changes
Other Study ID Numbers: SOLTI-1710
2019-001275-36 ( EudraCT Number )
First Posted: October 17, 2019    Key Record Dates
Last Update Posted: October 17, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by SOLTI Breast Cancer Research Group:
Palbociclib, residual disease, Neoadjuvant treatment, Ki67
Additional relevant MeSH terms:
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Neoplasm, Residual
Neoplastic Processes
Neoplasms
Pathologic Processes
Letrozole
Palbociclib
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Protein Kinase Inhibitors